Psoriasis is a chronic inflammatory, hyperproliferative disease of the skin, whose complex pathophysiology is determined by both environmental factors and genetic susceptibilities. Abnormalities in keratinocyte function, adaptive and innate immune cells, and cytokine production have been implicated in psoriasis. Human genetic studies have strongly linked single nucleotide polymorphisms (SNPs) of the gene TNFAIP3, also known as A20, to psoriasis susceptibility. Subsequent GWAS have replicated these associations. TNFAIP3 SNPs have also been linked to reduced A20 expression and therapeutic responses in patients. Our recent studies indicate that A20 restricts innate immune cells by regulating NF-B signals. We have also found that mice expressing reduced amounts of A20 are susceptible to imiquimod-induced psoriasis. Hence, our central hypothesis is that reduced A20 expression leads to perturbed innate immune, cytokine, and T cell functions and increased susceptibility to psoriasis. To test this hypothesis, we propose to first determine the cellular mechanisms by which A20 regulates psoriasis susceptibility using mice lacking or reduced A20 expression in dendritic cells, T cells, and epithelial cells. As we have found that A20 is a novel ubiquitin binding and ubiquitin modifying enzyme that interacts with other ubiquitin binding proteins, we will use novel A20 knock-in mice bearing strategic point mutations as well as mice lacking key A20 binding partners to test the physiological functions of these biochemical activities. These experiments should provide comprehensive and mechanistic insights into how A20 prevents psoriasis, and provide new areas for therapeutic discovery.
Psoriasis is the most common autoimmune disease, afflicting ~7.5 million Americans. Human genetic and clinical studies strongly link A20 to psoriasis susceptibility and clinical response. A20, also known as TNFAIP3, is a novel regulatory protein that restricts activation of immune cells. Hence, our studies investigating A20 in psoriasis models should provide compelling insights into the pathophysiology and potential cures for psoriasis.
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| Onizawa, Michio; Oshima, Shigeru; Schulze-Topphoff, Ulf et al. (2015) The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol 16:618-27 |
